GRANJAS COLECTIVAS

3.1.3.8 Fibrinogen. The fibrinogen level in the case group was greater than in the controls and in these two study groups it was normally distributed (Table 3.8). 3.1.3.9 Alcohol use. A slightly greater percentage of controls continued to use alcohol at the time of the interview (Table 3.9). Alcohol use is evaluated in more detail in Chapter 5.

3.1.3.10 Haematological measures. The case group had a significantly higher Hb and a lower MCV than the controls. The He, WCC, PT and APTT were not signifi­ cantly different between the two groups (Table 3.10).

3.1.4 Discussion

3.1.4.1 Sex as a risk factor. In populations in which CHD is a major health problem, the incidence of CHD is markedly lower in premenopausal women than in men, although there is a convergence after menopause. By the 8th decade the in­ cidence is almost equal in the two sexes.196 National mortality data in some Western countries suggests that the decreasing sex difference in CHD after 50 years of age is due to a declining rate of increase in men rather than an acceleration in women.196 This data suggests that factors other than age per se are more important in the devel­ opment of CHD, even though atherosclerosis continues to accumulate with age. The cause for the difference may be due to a mortality bias from premature deaths.

The relationship of risk factors to CHD also appears to be different in females. Women have m uch low er rates of CHD than men at the same values of cholesterol,198,405 menopause has an unfavourable effect on lipids,406 diabetes melli­ tus seems to be a greater risk factor for females than males407,408 and the genetic component to the liability to cardiac death may be greater in women.409 Women who die from CHD appear to have a similar relative risk but lower absolute and attribut­ able risk for smoking, diastolic BP and social class than men.405 However, the overall impact of CHD risk factors in women is poorly understood, the reason(s) for the different natural history are unknown and the pattern of risk associated with factors pertaining solely to women is even less well understood. Indeed, the evalua­ tion of CHD risk factors in longitudinal epidemiological studies indicate that some other factors protect women against CHD, such as natural oestrogen 405

Considering these and other concerns, it was considered prudent to again endeavour to make the study population as homogeneous as possible and initially exclude young women with CHD. The mothers of the two study groups had no significant differ­ ences in the incidence of CHD or CHD risk factors, although this may simply be a type II statistical error.

3.1.4.2 Age as a risk factor. Since aging itself is a well recognised and powerful risk factor for the developm ent o f CH D ,410 a group of m ales with prem ature CHD and a narrow age range and an age matched control group were selected to exclude the in flu en ce o f age on ath ero sclero sis and risk factors. In ad d itio n , ch o o sin g a young group w ould presum ably reduce the confounding effect o f the longer term influence of the major risk factors which themselves increase with age.161,202

3.1.4.3 Family history. A number of previous case-control studies have evaluat­ ed the fam ilial occurrence o f CHD as a primary objective.177"180,411'413 An increased risk of CHD in relatives of individuals with the disorder may in part be due to genet­ ic fa c to rs.177,411,413 This relationship was found to be highest w hen parental death from the disease occurred prem aturely,177,411 particularly in m ales who have both p a re n ts d y in g o f C H D .411 S im ila r p a tte rn s w ere n o t d e te c ta b le in o ld e r age

411 groups.

The familial com ponent for premature CHD is also related to the aggregation of risk factors in fa m ilie s.179,411 The m agnitude o f this contribution is controversial, w ith so m e s tu d ie s d e m o n s tr a tin g th is as the m a jo r o r to ta l c a u s e o f th e f a m ilia l p a tte rn .178,414,415 The relative im portance of the individual risk factors is sim ilarly v a ria b le .179,221,414,415 The inherent problem s in these studies is that a prim ary risk factor may reflect a genetic tendency to the m ajor risk factors, or a shared environ­ mental influence common within families.415 There may even be a familial aggrega­ tion for an increased susceptibility to the effects o f the major risk factors.415 N ever­ theless, support for case-control studies dem onstrating a separate association o f an independent genetic contribution is im pressive.170,188,416 In particular, prospective studies endorse the p o ssib ility o f h eritab le facto rs as im p o rtan t d eterm in an ts o f cardiovascular m ortality m ainly in younger m en ,171,181,188,417 and that CHD occurs p a r tly as a fa m ilia l d is o r d e r , p a r tic u la r ly e v id e n t in m a le s w ith p r e m a tu re C H D .171,181,188,417 One large p rospective study indicates that a history o f A M I in either parent is associated with an increased risk of CAD among men independent of diet or established risk factors.417 Indeed, the w eight of evidence indicates that the distinct fam ilial contribution to the m ajor risk factors fails to account for all o f the inherited component188,416 and that other familial risk factors remain to be found.416 The prim ary aim o f this present study was not to exam ine fam ilial aggregation of CHD. The study num ber is too small to evaluate the independence o f such an asso­ ciatio n by adjusting fo r o th er CHD risk factors. Further, a po sitiv e recall bias in those having an AMI cannot be controlled for without independent validation of the subjects personal observations and recollections.

The significantly increased incidence o f paternal CHD in this study is concordant w ith the lite ra tu re . H o w ev er, this o b serv atio n , and that fo r the sib lin g s and the m aternal history, cannot be interpreted as a positive or negative finding in view o f the limitations discussed above. However, the selection of young males as the study population was in part m otivated by the evidence that premature CHD in males does have a significant and independent fam ilial aggregation,181,188,416,418 which is unex­ p la in e d . T he selectio n o f such a group m ay th erefo re in crease the p o ssib ility o f d etectin g such u n id en tified risk factors by reducing the "noise" from in teractiv e confounding factors and heterogeneous study populations.

3.1.4.4 Lipoproteins. A relationship between increased platelet aggregability and platelet reactivity with dyslipoproteinaem ias has been well established,126,128,419'426 highlighting the im portance o f carefully docum enting the lipoprotein profile o f the study group. This aspect is discussed in Chapter 5.

3.1.4.5 Hypertension. It also appears possible that a relationship between BP and platelet aggregation exists.145' 147 The fact that hypertension was treated, particularly in the case group, many of whom were on vasoactive medications for other reasons, may be a potentially im portant confounding factor which cannot be effectively con­ trolled for in this cross-sectional study. Appropriate interpretation of the results must be made given this potential major bias.

3.1.4.6 Blood glucose. R aised plasm a adrenaline and hyperglycaem ia after MI may activate platelets, and this could contribute to a poor outcome in such patients.75 A relationship between platelet function and abnorm al glucose m etabolism is well established, although not fully clarified, and illustrates the necessity for excluding d iab etic individuals. Since abnorm al glucose hom eostasis may play a role in the path o g en esis o f CHD, even in non-diabetics, an evaluation o f relatio n sh ip s w ith glucose haemostasis has been undertaken. This aspect is discussed in Appendix 2. 3 .1.4.7 Tobacco use. Previous studies have suggested that platelets may be acti­ vated during chronic cigarette smoking57,427,428 and that the metabolism of platelets is altered. For example, increased production o f thromboxane may be a direct effect of smoking.428,429 Furthermore, there appears to be an acute effect of cigarette smoking on in vitro*30,122 and in vivo platelet function, although this is co n tro v ersial.431,432 Smoking cessation lessons the risk of death or MI in older and younger persons with C A D .433 Indeed, the increased risk o f a first MI among cigarette sm okers declines soon after cessation, both for men and women, and is largely dissipated within two or three y ears.434 In fact, the risk o f sm oking w ould appear to be asso ciated only w ith c u rren t sm oking, and the duration o f the sm oking habit is less im p o rtan t.435 M oreover, non-atherogenic m echanism s m ay be im portant in the aetiology o f MI am ong w om en who are cig arette sm okers.436 A rap id reg ressio n in risk o f CHD w ithin the first year of quitting smoking is difficult to explain solely on the basis of vascular disease,429 and may be related to a reversal in abnormalities o f platelet and haemostatic function.429

In this study, very few controls or cases w ere current tobacco users. T herefore, in light o f the foregoing discussion, there is a high probability that the study may suffer from the confounding influence resu ltin g from the cessation o f sm oking. On the other hand, the fact that the majority did not use tobacco at the time o f the evalua­ tion, enables the detection o f any abnormal platelet function in the case group inde­ pendent o f acute tobacco use.

3 .1.4.8 Cardiac medications. Beta-blockers w ithout intrinsic sympathomimetic activity are associated with an increase in the triglyceride level and a decrease in the H D L cholesterol level.389 Despite these unfavourable changes, after AMI, there is a reduction in risk associated with the use of beta-blockers.389 Thiazides also influence lipids, resulting in an increase in total cholesterol.437 The longterm outcome o f these ch an g es are unknow n.438 M ore im portantly, a num ber o f cardiac drugs influence

platelet function in vitro and may do so in vivo as well. Therefore, a separate evalua­ tion of the influence of the more common types of cardiac medications was under­ taken as a preliminary evaluation. The results are presented and discussed in Chapter 4.

3.1.4.9 Conclusion. This section details important comparisons between the two groups in this case-control study, in particular with regards to the major risk factors for CHD. It is clear that the differences between the two groups are consistent with those found in the literature and clinical practice. Important potential confounding factors apparent from these results are the differences in the lipoproteins, glucose homeostasis, plasma fibrinogen levels, possibly previous tobacco consumption and BP levels. Furthermore, methodological bias may arise from the greater use of cardiac drugs in the case group. These issues of methodological bias and the pres­ ence of confounding factors are addressed in Chapters 4 and 8.

3.2 MARITAL STATUS, EDUCATION AND EMPLOYMENT